US9187521B2 - Tubulysins and processes for preparing - Google Patents
Tubulysins and processes for preparing Download PDFInfo
- Publication number
- US9187521B2 US9187521B2 US12/739,579 US73957908A US9187521B2 US 9187521 B2 US9187521 B2 US 9187521B2 US 73957908 A US73957908 A US 73957908A US 9187521 B2 US9187521 B2 US 9187521B2
- Authority
- US
- United States
- Prior art keywords
- alkyl
- formula
- aryl
- alkenyl
- optionally substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
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- 238000000034 method Methods 0.000 title claims abstract description 61
- 230000008569 process Effects 0.000 title claims abstract description 50
- 229930184737 tubulysin Natural products 0.000 title abstract description 129
- 125000000217 alkyl group Chemical group 0.000 claims description 161
- 125000003118 aryl group Chemical group 0.000 claims description 106
- 150000001875 compounds Chemical class 0.000 claims description 103
- 125000003342 alkenyl group Chemical group 0.000 claims description 87
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 60
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 60
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 150000001768 cations Chemical class 0.000 claims description 25
- -1 cyano, hydroxyl Chemical group 0.000 claims description 25
- 229910052751 metal Inorganic materials 0.000 claims description 25
- 239000002184 metal Substances 0.000 claims description 25
- HWCIETDQUHYHGQ-YHVCZDCZSA-N Tubulysin B Chemical compound C([C@@H](C[C@H](C)C(O)=O)NC(=O)C=1N=C(SC=1)[C@H](OC(C)=O)C[C@@H](N(COC(=O)CCC)C(=O)[C@@H](NC(=O)[C@@H]1N(CCCC1)C)[C@@H](C)CC)C(C)C)C1=CC=C(O)C=C1 HWCIETDQUHYHGQ-YHVCZDCZSA-N 0.000 claims description 19
- HWCIETDQUHYHGQ-UHFFFAOYSA-N tubulysin B Natural products C1CCCN(C)C1C(=O)NC(C(C)CC)C(=O)N(COC(=O)CCC)C(C(C)C)CC(OC(C)=O)C(SC=1)=NC=1C(=O)NC(CC(C)C(O)=O)CC1=CC=C(O)C=C1 HWCIETDQUHYHGQ-UHFFFAOYSA-N 0.000 claims description 19
- 108010061146 tubulysin B Proteins 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 15
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 15
- 125000001188 haloalkyl group Chemical group 0.000 claims description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000012038 nucleophile Substances 0.000 claims description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 8
- 229940002612 prodrug Drugs 0.000 claims description 8
- 239000000651 prodrug Chemical group 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 5
- LJDZFAPLPVPTBD-UHFFFAOYSA-N nitroformic acid Chemical compound OC(=O)[N+]([O-])=O LJDZFAPLPVPTBD-UHFFFAOYSA-N 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- 150000001450 anions Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 239000000203 mixture Substances 0.000 abstract description 59
- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 abstract description 54
- 201000010099 disease Diseases 0.000 abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 230000001717 pathogenic effect Effects 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 0 [1*]C(=O)OCN(C(=O)[C@@H](NC(=O)[C@H]1CCCCN1C)C(C)CC)[C@H](C[C@@H](OC(C)=O)C1=NC(C(=O)N[C@@H](CC2=CC=C([3H])C=C2)C[C@H](C)C(=O)O)=CS1)C(C)C Chemical compound [1*]C(=O)OCN(C(=O)[C@@H](NC(=O)[C@H]1CCCCN1C)C(C)CC)[C@H](C[C@@H](OC(C)=O)C1=NC(C(=O)N[C@@H](CC2=CC=C([3H])C=C2)C[C@H](C)C(=O)O)=CS1)C(C)C 0.000 description 48
- 239000000543 intermediate Substances 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- 125000005843 halogen group Chemical group 0.000 description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 150000003839 salts Chemical class 0.000 description 17
- 229910052717 sulfur Inorganic materials 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 14
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 14
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 14
- 229910052786 argon Inorganic materials 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 229910052770 Uranium Inorganic materials 0.000 description 10
- 125000004093 cyano group Chemical group *C#N 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 8
- 235000019152 folic acid Nutrition 0.000 description 8
- 239000011724 folic acid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000003643 water by type Substances 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 6
- 229960000304 folic acid Drugs 0.000 description 6
- 239000012064 sodium phosphate buffer Substances 0.000 description 6
- 150000001735 carboxylic acids Chemical class 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 241000894007 species Species 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 4
- IBEDDHUHZBDXGB-OEJISELMSA-N Tubulysin A Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(O)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C IBEDDHUHZBDXGB-OEJISELMSA-N 0.000 description 4
- IBEDDHUHZBDXGB-UHFFFAOYSA-N Tubulysin A Natural products N=1C(C(=O)NC(CC(C)C(O)=O)CC=2C=CC(O)=CC=2)=CSC=1C(OC(C)=O)CC(C(C)C)N(COC(=O)CC(C)C)C(=O)C(C(C)CC)NC(=O)C1CCCCN1C IBEDDHUHZBDXGB-UHFFFAOYSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical class [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 4
- 108010061145 tubulysin A Proteins 0.000 description 4
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
- 238000010600 3H thymidine incorporation assay Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 229910004749 OS(O)2 Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
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- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- PCLMSUBZTGCHQT-WCBMZHEXSA-N (2s,4r)-4-amino-5-(4-hydroxyphenyl)-2-methylpentanoic acid Chemical compound OC(=O)[C@@H](C)C[C@@H](N)CC1=CC=C(O)C=C1 PCLMSUBZTGCHQT-WCBMZHEXSA-N 0.000 description 2
- TVHNWAKCVXFPNB-HCCKASOXSA-N (4r)-4-amino-2-methyl-5-phenylpentanoic acid Chemical compound OC(=O)C(C)C[C@@H](N)CC1=CC=CC=C1 TVHNWAKCVXFPNB-HCCKASOXSA-N 0.000 description 2
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 2
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- BPSLZWSRHTULGU-UHFFFAOYSA-N Methylpipecolic acid Chemical compound CN1CCCCC1C(O)=O BPSLZWSRHTULGU-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- LKKIBSZFPLXREY-LYWCUUMRSA-N [[(1r,3r)-1-acetyloxy-4-methyl-1-[4-[[(2r,4s)-4-methyl-1-(4-methylphenyl)-5-oxo-5-[2-[2-(pyridin-4-yldisulfanyl)ethoxycarbonyl]hydrazinyl]pentan-2-yl]carbamoyl]-1,3-thiazol-2-yl]pentan-3-yl]-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]p Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(=O)NNC(=O)OCCSSC=1C=CN=CC=1)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C LKKIBSZFPLXREY-LYWCUUMRSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
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- 230000000259 anti-tumor effect Effects 0.000 description 2
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- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
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- 241000863009 Archangium gephyra Species 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
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- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Substances CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
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- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
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- 238000006257 total synthesis reaction Methods 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 108010061212 tubulysin D Proteins 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
Definitions
- the invention described herein pertains to tubulysins and tubulysin analogs, and processes for preparing tubulysins and tubulysin analogs.
- Tubulysins are a group of powerful inhibitors of tubulin polymerization. Tubulysins are useful in treating diseases and disease states that include pathogenic cell populations, such as cancer. Generally, tubulysins are linear tetrapeptides consisting of N-methyl pipecolic acid (Mep), isoleucine (Ile), an unnatural aminoacid called tubuvalin (Tuv), and either an unnatural aminoacid called tubutyrosine (Tut, an analog of tyrosine) or an unnatural aminoacid called tubuphenylalanine (Tup, an analog of phenylalanine), as shown in the following table:
- one species Archangium gephyra , produces as the main component factors tubulysins A, B, C, G, and I, each of which may be identified by its including the Tut residue.
- another species Angiococcus disciformis , produces as the main component factors tubulysins D, E, F, and H, each of which may be identified by its including the Tup residue.
- tubulysins Such bacterial fermentations are convenient sources of tubulysins.
- mycobacteria produce only certain tubulysins, and/or mixtures of tubulysins, processes are needed for interconverting those tubulysins to the desired factors for medicinal and pharmacological uses.
- processes are needed for preparing novel tubulysins, tubulysin analogs, and tubulysin derivatives for medicinal and pharmacological uses.
- processes for preparing tubulysins are also described herein are analogs and derivatives of tubulysins.
- processes are described for preparing one or more tubulysins from a mixture of tubulysins, such as a mixture of tubulysins produced by fermentation or some other process.
- processes are described herein for preparing a mixture of tubulysins from one or more tubulysins.
- processes are described herein for converting one tubulysin into another tubulysin.
- processes are described herein for converting one or more, or a mixture of tubulysins into one or more, or a mixture of tubulysin analogs.
- tubulysin refers both collectively and individually to the naturally occurring tubulysin, and the analogs and derivatives of tubulysins described herein, or that may be prepared from the processes described herein.
- novel tubulysins, tubulysin analogs, and tubulysin derivatives are described herein along with processes for preparing such novel tubulysins, tubulysin analogs, and tubulysin derivatives.
- the processes include treating one or more tubulysins with an acid to prepare an intermediate.
- the processes include the step of subsequently reacting the intermediate with a reagent to prepare a mixture of tubulysins from a different mixture of tubulysins, a single tubulysin from a mixture of tubulysins, a mixture of tubulysins from a single tubulysin, or a single tubulysins from a different tubulysin.
- the intermediate is a compound of formulae (1a), (1b), or (1c):
- R, R 1 , S, T, U, V, W, Y, and Z are as described hereinbelow in the various embodiments, aspects, and variations thereof.
- intermediate compounds of formulae (1a), (1b), and (1c) may form salts, such as salts with the residual acid conjugate base.
- iminium intermediates such as those of formulae (1a), (1b), and (1c) may also be in equilibrium with the corresponding acyl aminal, where the residual acid conjugate base adds to the iminium intermediate.
- the iminium intermediates may form solvates or hydrates, each of which may be in equilibrium with the iminium intermediates.
- nucleophiles such as RCN, RXH and the corresponding anions and salts thereof react with iminium intermediates regardless of whether the iminium is in a salt, hydrate, solvate or acylaminal form to prepare the compounds described herein, such as the compounds of formulae (2a), (2b), and (2c), respectively:
- R, R 1 , R 10 , S, T, U, V, W, Y, and Z are as described hereinbelow in the various embodiments, aspects, and variations thereof.
- tubulysins described herein refer generally to tetrapeptide compounds of the formula
- n 1-3;
- V is H, OR 2 , or halo
- W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, and C(O)R 3 , where R 3 is alkyl, cycloalkyl, alkenyl, aryl, or arylalkyl, each of which is optionally substituted; providing that R 2 is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl;
- Z is alkyl and Y is O; or Z is alkyl or C(O)R 4 , and Y is absent, where R 4 is alkyl, CF 3 , or aryl;
- R 1 is H, or R 1 represents 1 to 3 substituents selected from halo, nitro, carboxylate or a derivative thereof, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, phenol protecting groups, prodrug moieties, and OR 6 , where R 6 is optionally substituted aryl, C(O)R 7 , P(O)(OR 8 ) 2 , or SO 3 R 8 , where R 7 and R 8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8 is a metal cation; and
- R is OH or a leaving group, or R forms a carboxylic acid derivative.
- Z is methyl.
- R 1 is H.
- R 1 is OR 6 at C(4), where R 6 is H, alkyl, or COR 7 .
- V is H, and W is OC(O)R 3 .
- Illustrative leaving groups include, but are not limited to halides, sulfonates, such as triflates, and the like, optionally substituted phenoxy, such as pentafluorophenoxy and the like, intermediates formed from ester forming or amide forming reagents, such as isobutyl chloroformate, DCC, HOBt, EDC, PyBOP, BOP, BOP-Cl, and the like.
- Illustrative carboxylic acid derivatives include, but are not limited to, esters, amides, imides, acylhydrazides, nitriles, and optionally substituted variations thereof.
- tubulysins of the following general formula are described
- n 1-3;
- V is H, OR 2 , or halo
- W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, or C(O)R 3 , where R 3 is alkyl, alkenyl or aryl, providing that R 2 is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl;
- Z is alkyl or C(O)R 4 , where R 4 is alkyl, CF 3 , or aryl;
- T is H or OR 6 , where R 6 is H, alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 , or SO 3 R 8 , where R 7 and R 8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8 is a metal cation, or R 6 is a phenol protecting group, or a prodrug moiety;
- S and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy;
- R is OH or a leaving group, or R forms a carboxylic acid derivative.
- natural tubulysins and the corresponding analogs and derivatives thereof are described.
- Such natural tubulysins are generally linear tetrapeptides consisting of N-methyl pipecolic acid (Mep), isoleucine (Ile), an unnatural aminoacid called tubuvalin (Tuv), and either an unnatural aminoacid called tubutyrosine (Tut, an analog of tyrosine) or an unnatural aminoacid called tubuphenylalanine (Tup, an analog of phenylalanine).
- naturally occurring tubulysins, and analogs and derivatives thereof, of the following general formula are described
- R, R 1 , and R 10 are as described in the various embodiments herein.
- a first tubulysin or alternatively a mixture of tubulysins, is converted into a second tubulysin by preparing an intermediate compound of formula (1a), wherein
- n 1-3;
- V is H, OR 2 , or halo
- W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, and C(O)R 3 , where R 3 is alkyl, cycloalkyl, alkenyl, aryl, or arylalkyl, each of which is optionally substituted; providing that R 2 is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl;
- Z is alkyl and Y is O; or Z is alkyl or C(O)R 4 , and Y is absent, where R 4 is alkyl, CF 3 , or aryl;
- R 1 is H, or R 1 represents 1 to 3 substituents selected from halo, nitro, carboxylate or a derivative thereof, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, phenol protecting groups, prodrug moieties, and OR 6 , where R 6 is optionally substituted aryl, C(O)R 7 , P(O)(OR 8 ) 2 , or SO 3 R 8 , where R 7 and R 8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8 is a metal cation; and
- R is OH or a leaving group, or R forms a carboxylic acid derivative.
- the intermediate is prepared by mixing a tubulysin or mixture of tubulysins of formula (2b) with an acid under substantially anhydrous conditions:
- n 1-3;
- V is H, OR 2 , or halo
- W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, and C(O)R 3 , where R 3 is alkyl, cycloalkyl, alkenyl, aryl, or arylalkyl, each of which is optionally substituted; providing that R 2 is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl;
- Z is alkyl and Y is O; or Z is alkyl or C(O)R 4 , and Y is absent, where R 4 is alkyl, CF 3 , or aryl;
- R 1 is H, or R 1 represents 1 to 3 substituents selected from halo, nitro, carboxylate or a derivative thereof, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, phenol protecting groups, prodrug moieties, and OR 6 , where R 6 is optionally substituted aryl, C(O)R 7 , P(O)(OR 8 ) 2 , or SO 3 R 8 , where R 7 and R 8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8 is a metal cation; and
- R is OH or a leaving group, or R forms a carboxylic acid derivative.
- the intermediate compound of formula (1a) is then treated with a compound of formula R 10 CO 2 H, where R 10 is not the same as R 10 present in the first tubulysin used to prepare the second compound of formula (2a).
- Z is methyl.
- R 1 is H.
- R 1 is OR 6 at C(4), where R 6 is H, alkyl, or COR 7 .
- V is H, and W is OC(O)R 3 .
- R is OH.
- R forms an ester derivative.
- R forms an amide derivative.
- R forms an acylhydrazide derivative, such as the compound formed from hydrazine.
- a first tubulysin is converted into a second tubulysin by preparing an intermediate compound of formula (1b), wherein V is H, OR 2 , or halo, and W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, or COR 3 , where R 3 is alkyl, alkenyl or aryl, providing that R 2 is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl; Z is CH 3 or COR 4 , and Y is absent; or Z is CH 3 and, Y is O; where R 4 is alkyl, CF 3 or aryl; T is H or OR 6 , where R 6 is H, alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 , or SO 3 R 8 , where R 7 and R 8 are independently selected in each instance
- R 10 is H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted;
- V is H, OR 2 , or halo, and W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, or COR 3 , where R 3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R 2 is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl;
- Z is CH 3 or COR 4 , and Y is absent; or Z is CH 3 and, Y is O; where R 4 is alkyl, CF 3 or aryl;
- T is H or OR 6 , where R 6 is H, alkyl, aryl, COR 7 , P(O)(OR 8 ) 2
- a first tubulysin or a mixture of tubulysins is converted into a second tubulysin by preparing an intermediate compound of formula (1c), wherein T is H or OH.
- the intermediate is prepared by mixing a tubulysin or mixture of tubulysins of formula (2c) with an acid under substantially anhydrous conditions:
- T is H or OH and R 10 is H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- R 10 is then treated with a compound of formula R 10 CO 2 H where R 10 is not the same as R 1 present in the starting tubulysin used to prepare the second compound of formula (2c).
- tubulysins may instead be converted into different mixtures of tubulysins rather than a single tubulysin.
- a single starting tubulysin, or mixture of tubulysins may be first converted into a common intermediate compound or a mixture of intermediate compounds of formulae (1a), (1b), or (1c), then those intermediate compounds are reacted with a mixture of carboxylic acids to provide the desired mixture of tubulysins.
- tubulysin A a single starting tubulysin, such as tubulysin A, or the corresponding analog or derivative thereof, or alternatively a mixture of tubulysins
- a single starting tubulysin such as tubulysin A, or the corresponding analog or derivative thereof, or alternatively a mixture of tubulysins
- T is OH
- carboxylic acids such as butanoic acid and propanoic acid
- intermediate compound of formula (1b) can be treated with a compound of formula R 9 QH or the anion prepared therefrom to give a compound of the following formula:
- R 9 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted, or R 9 is C(O)R 20 , S(O) 2 R 20 , or P(O)(OR 20 ) 2 ; where R 20 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R 20 is a metal cation; V is H, OR 2 , or halo, and W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, or COR 3 , where R 3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R 2 is
- intermediate compound of formula (1c) can be treated with a compound of formula R 9 QH or an anion thereof to give a compound of the following formula:
- R 9 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted, or R 9 is C(O)R 20 , S(O) 2 R 20 , or P(O)(OR 20 ) 2 ; where R 20 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R 20 is a metal cation: and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- intermediate compound of formula (1b) can be treated with a nitrile compound, R 21 CN, to give a compound of the following formula:
- R 21 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted;
- intermediate compound of formula (1c) can be treated with a nitrile compound, R 21 CN, to give a compound of the following formula:
- R 21 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- intermediate compound of formula (1b) can be treated with an alkenylsilane of formula R 22 (TMS)CCH 2 to give a compound of the following formula:
- R 22 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted;
- V is H, OR 2 , or halo, and W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, or COR 3 , where R 3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R 2 is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl;
- Z is CH 3 or COR 4 , and Y is absent; or Z is CH 3 and, Y is O; where R 4 is alkyl, CF 3 or aryl;
- T is H or OR 6 , where R 6 is H, alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 ,
- intermediate compound of formula (1c) can be treated with an alkenylsilane of formula R 22 (TMS)CCH 2 to give a compound of the following formula:
- R 22 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- olefins may form by isomerization, depending on the conditions of the reaction and the identity of R 22 .
- R 22 is alkyl
- the double bond can migrate to other carbon atoms along the alkenyl chain, including to form the terminal or ⁇ -olefin.
- intermediate compound of formula (1b) is treated with a compound of formula R 23 C(O)CH 2 R a to give a compound of the following formula:
- R 23 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted;
- R a is C(O)R 9 , C(O)OR 9 or CN;
- R 9 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted;
- V is H, OR 2 , or halo
- W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, or COR 3 , where R 3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R 2 is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl;
- Z is CH 3 or COR 4
- intermediate compound of formula (1c) is treated with a compound of formula R 23 C(O)CH 2 R a to give a compound of the following formula:
- R 23 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted;
- R a is C(O)R 9 , C(O)OR 9 or CN;
- R 9 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted: and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- intermediate compound of formula (1b) is treated with water to give a second intermediate compound of the following formula (3b)
- V is H, OR 2 , or halo
- W is H, OR 2 , or alkyl
- R 2 is independently selected in each instance from H, alkyl, or COR 3 , where R 3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R 2 is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl
- Z is CH 3 or COR 4 , and Y is absent; or Z is CH 3 and, Y is O; where R 4 is alkyl, CF 3 or aryl
- T is H or OR 6 , where R 6 is H, alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 , or SO 3 R 8 , where R 7 and R 8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl,
- intermediate compound of formula (1c) is treated with water to give a second intermediate compound of formula (3c):
- T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- intermediate compound of formula (3b) is treated with a halogenating, sulfonylating, phosphonylating or phosphorylation reagent to give a compound of the following formula:
- X 3 is halogen, OS(O) 2 R 24 , OP(O)(OR 24 )R 24 , or OP(O)(OR 24 ) 2 ; where R 24 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R 24 is a metal cation; V is H, OR 2 , or halo, and W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, or COR 3 , where R 3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R 2 is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl; Z is CH 3 or COR 4 , and Y is absent; or Z
- intermediate compound of formula (3c) is treated with a halogenating, sulfonylating, phosphonylating or phosphorylation reagent to give a compound of the following formula:
- X 3 is halogen, OS(O) 2 R 24 , OP(O)(OR 24 )R 24 , or OP(O)(OR 24 ) 2 ; where R 24 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R 24 is a metal cation; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- the corresponding compounds of formula (3a) may be similarly prepared via the corresponding intermediate of formula (1a) and treatment with a halogenating, sulfonylating, phosphonylating or phosphorylation reagent.
- R 10 is H, alkyl, cycloalkyl, alkenyl, aryl or arylalkyl, each of which is optionally substituted: and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH; is treated with trifluoroacetic acid and the mixture is concentrated under reduced pressure to give an intermediate iminium compound.
- iminium compounds may be present as the corresponding trifluoroacetate salt compounds, and other hydrates and solvates, and as the acylaminal compound, and other addition adducts, as is illustrated by the following formulae:
- R 9 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted, or R 9 is C(O)R 20 , S(O) 2 R 20 , or P(O)(OR 20 ) 2 ; where R 20 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R 20 is a metal cation: and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- R 9 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted, or R 9 is C(O)R 20 , S(O) 2 R 20 , or P(O)(OR 20 ) 2 ; where R 20 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R 20 is a metal cation: and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- R 21 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- R 23 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted;
- R a is C(O)R 8 , C(O)OR 8 or CN;
- R 8 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted;
- T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- R 22 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- hydroxytubulysin D when T is OH
- hydroxytubulysin A when T is OH
- R is other than OH
- N-hydroxymethylubulysin A or N-hydroxymethylubulysin D is treated with a sulfonyl halide and a base to give a compound of the following formula:
- R 24 is alkyl, cycloalkyl, alkenyl, aryl or arylalkyl, each of which is optionally substituted; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
- N-hydroxymethylubulysin A or N-hydroxymethylubulysin D is treated with a bromine or iodine in the presence of triphenylphospine and imidazole to give a compound of the following formula:
- conjugates of tubulysins of the following formula are described:
- T is H or OR 6 , where R 6 is H, alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 , or SO 3 R 8 , where R 7 and R 8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8 is a metal cation, or R 6 is a phenol protecting group, or a prodrug moiety;
- Z is alkyl or C(O)R 4 , where R 4 is alkyl, CF 3 , or aryl; and R is OH or a leaving group, or R forms a carboxylic acid derivative.
- conjugates described herein may include spacer linkers and/or releasable linkers as generally described in US Patent Application Publication 2005/0002942, the disclosure of which is incorporated herein by reference.
- conjugates described herein may include targeting ligands, including but not limited to folate and analogs and derivatives of folate, for targeting the conjugates to pathogenic cell populations, such as generally described in US Patent Application Publication 2005/0002942.
- tubulysins of the following general formula are described
- n 1-3;
- V is H, OR 2 , or halo
- W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, or COR 3 , where R 3 is alkyl, alkenyl or aryl, providing that R 2 is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl;
- Z is CH 3 or COR 4 , and Y is absent; or Z is CH 3 and, Y is O; where R 4 is alkyl, CF 3 or aryl;
- T is H or OR 6 , where R 6 is H, alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 , or SO 3 R 8 , where R 7 and R 8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8 is a metal cation;
- S and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy;
- R is OH or a leaving group, or R forms a carboxylic acid derivative. Additional tubulysins are described in US patent application publication Nos. 2006/0128754 and 2005/0239713, the disclosures of which are incorporated herein by reference.
- tubulysins of the following formula are described:
- T is H or OR 6 , where R 6 is H, alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 , or SO 3 R 8 , where R 7 and R 8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8 is a metal cation, or R 6 is a phenol protecting group, or a prodrug moiety;
- Z is alkyl or C(O)R 4 , where R 4 is alkyl, CF 3 , or aryl; and R is OH or a leaving group, or R forms a carboxylic acid derivative.
- tubulysins of the following formula are described:
- n, S, T, U, V, W, Z, R, and R 10 are as described in the various embodiments herein.
- tubulysins of the following formula are described:
- n, S, T, U, V, W, Z, QR 9 , and R are as described in the various embodiments herein.
- Q is —N—, —O—, or —S—; and R 9 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted.
- QR 9 are taken together to form C(O)R 10 , S(O) 2 R 10 , P(O)(OR 10a ) 2 , where R 10 and OR 10a are independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R 10a is a metal cation.
- tubulysins of the following formula are described:
- R 12 represents 1 or more substituents selected from alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted; and where n, S, T, U, V, W, Z, and R are as described in the various embodiments herein.
- R 1 represents 1 or more substituents selected from alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted
- n, S, T, U, V, W, Z, and R are as described in the various embodiments herein.
- R 1 is alkyl
- the double bond can migrate to other carbon atoms along the alkenyl chain, including to form the terminal or ⁇ -olefin.
- tubulysins of the following formula are described:
- R 13 is C(O)R 10 , C(O)OR 10 or CN; and where n, S, T, U, V, W, Z, R, and R 10 are as described in the various embodiments herein, where R 10 is independently selected in each instance.
- tubulysins of the following formula are described:
- n, S, T, U, V, W, Z, and R are as described in the various embodiments herein.
- tubulysins of the following formula are described:
- X 3 is halogen, OS(O) 2 R 10 , OP(O)(OR 10a )R 10 , or OP(O)(OR 10a ) 2 ; where R 10 and R 10a are independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R 10a is a metal cation; and where n, S, T, U, V, W, Z, and R are as described in the various embodiments herein.
- tubulysins useful in preparing the conjugates described herein are described in Peltier et al., “The Total Synthesis of Tubulysin D,” J. Am. Chem. Soc. 128:16018-19 (2006), the disclosure of which is incorporated herein by reference.
- tubulysin compounds may be inhibitors of tubulin polymerization, and also may be DNA-alkylators. Accordingly, methods for treating diseases and disease states including pathogenic cell populations, such as cancer, are described herein.
- Trifluoroacetic acid (TFA, 0.20 mL) was added via syringe into a light brown solution of a tubulysin mixture (20 mg, containing tubulysins A, B, C, G, I and hydroxytubulysin) in anhydrous dichloromethane (DCM, 0.80 mL).
- the corresponding nucleophile for example, but not limited to, H 2 O, MeOH, 1-propanol, ethylene glycol, 3-methylbutanol, 1-propanethiol, 2-sulfanylethanol, 1,2-ethanedithiol, acetic acid, butyric acid, trans-4-chloro-2-butenoic acid
- 0.20 mL was used for all thiols and 0.50 mL was used for all the others, and the solution was concentrated at reduced pressure on a Büchi Rotavapor and then further concentrated by means of an oil pump.
- the crude product was dissolved in dimethyl sulfoxide (DMSO, 1.0 mL) and purified by preparative HPLC to afford the product as a white solid.
- DMSO dimethyl sulfoxide
- HPLC analysis indicated a complete conversion of the hydroxy tubulysin intermediate to tubulysin B.
- the crude product was dissolved in DMSO (1.2 mL) and purified by preparative HPLC on a Waters XTerra Prep MS C 18 10 ⁇ m 19 ⁇ 250 mm column using a 25% B to 50% B gradient over 20 minutes (A: 2.0 mM phosphate buffer, pH 7.0; B: ACN) at 25 mL/minute. Fractions from 11.5 to 13.5 minutes were collected and lyophilized to 86 mg of a white solid containing 77 mg of tubulysin B and 9.0 mg of sodium phosphate salts.
- tubulysin B As compared to a reference standard sample. It is to be understood that other mixtures of tubulysins can be similarly converted into a single tubulysin. It is further to be understood that this and other mixtures of tubulysins can be similarly converted into a different tubulysin than tubulysin B.
- EXAMPLE Interconversion of natural tubulysins.
- the conditions of the previous Example were repeated to (a) convert tubulysin A into tubulysin B, (b) convert tubulysin A into tubulysin I, (c) convert a mixture of tubulysins A and B into tubulysin B, and (d) convert a mixture of tubulysins A, B, and I into tubulysin B.
- the yield of tubulysin B was ⁇ 90%. It is to be understood that in each of examples (a) to (d), the corresponding tubulysin can be converted into a different tubulysin than tubulysin B.
- tubulysin B can be similarly converted into a different tubulysin.
- N-hydroxymethyl substituted tubulysin was also isolated. It was surprisingly discovered that this hemiaminal was stable at neutral pH, and did not decompose to the free amine and formaldehyde.
- R C(O)CH 2 CH(CH 3 ) 2 , C(O)CH 2 CH 2 CH 3 , C(O)CH 2 CH 3 , C(O)CH ⁇ C(CH 3 ) 2 , C(O)CH 3 , and H, respectively
- TFA (0.15 mL) was added to a solution of the tubulysin mixture (19 mg) in anhydrous DCM (0.60 mL) at room temperature. After stirring for 40 minutes at room temperature under argon, the reaction was quenched with anhydrous MeOH (0.50 mL).
- the solution was concentrated on a Büchi Rotavapor, co-evaporated with anhydrous MeOH (2 ⁇ ) and anhydrous DCM (2 ⁇ ), vacuumed for 30 minutes, co-evaporated again with anhydrous MeOH and anhydrous DCM (2 ⁇ ), and vacuumed for an additional 1.5 hours.
- the residue was dissolved in anhydrous DCM (0.75 mL), to which was added allyltrimethylsilane (0.30 mL), cooled in an ice-bath, and to which was added BF 3 .Et 2 O (0.23 mL).
- the reaction mixture was stirred under argon in an ice-bath for 30 minutes, and then the cooling was removed and the reaction mixture was stirred at room temperature for an additional 2 hours and 50 minutes.
- N,N-Diisopropylethylamine (DIPEA, 6.1 ⁇ L) and isobutyl chloroformate (3.0 ⁇ L) were added with the help of a syringe in tandem into a solution of tubulysin B (0.15 mg) in anhydrous EtOAc (2.0 mL) at ⁇ 15° C.
- EtOAc 2.0 mL
- the reaction mixture was cooled down to ⁇ 20° C. and to which was added anhydrous hydrazine (5.0 ⁇ L).
- the reaction mixture was stirred under argon at ⁇ 20° C.
- additional tubulysin compounds and analogs and derivatives thereof.
- additional ether forming alcohols may be used, including but not limited to alcohols, such as ethanol, propanol, sec-butanol, and the like, polyols, such as ethylene glycols, polyethylene glycols, propylene glycols, polypropylene glycols, glycerol, and the like, including alkyl, and acyl derivatives thereof, aminoalcohols, such as aminoethanol, aminopropanol, polyaminoalkylethanol, and the like, including alkyl, and acyl derivatives thereof, and others.
- additional thiols, carboxylic acids, amino acids, amines, and the like may be used as nucleophiles to trap the intermediate iminium compounds of formulae (1) and (3).
- METHOD EXAMPLE Inhibition of Cellular DNA Synthesis.
- the compounds described herein are evaluated using an in vitro cytotoxicity assay that predicts the ability of the drug to inhibit the growth of folate receptor-positive KB cells.
- the KB cells are exposed for up to 7 h at 37° C. over a range of concentrations of folate-drug conjugate in the absence or presence of at least a 100-fold excess of folic acid.
- the cells are then rinsed once with fresh culture medium and incubated in fresh culture medium for 72 hours at 37° C. Cell viability is assessed using a 3 H-thymidine incorporation assay.
- METHOD EXAMPLE In vitro concentration-dependent cytotoxic activity. Cells were heavily seeded in 24-well Falcon plates and allowed to form nearly confluent monolayers overnight. Thirty minutes prior to the addition of test article, spent medium was aspirated from all wells and replaced with fresh folate-free RPMI (FFRPMI). Note, designated wells received media containing 100 ⁇ M folic acid; and, cells within the latter wells were used to determine the targeting specificity, since cytotoxic activity produced in the presence of excess folic acid (enables competition for FR binding) would signify the portion of the total activity that was unrelated to FR-specific delivery.
- FFRPMI folate-free RPMI
- each well received 1 mL of media containing increasing concentrations of test article (4 wells per sample) in the presence or absence of 100 ⁇ M free folic acid (a binding site competitor).
- Treated cells were pulsed for 2 h at 37° C., rinsed 4 times with 0.5 mL of media, and then chased in 1 mL of fresh media up to 70 h. Spent media was aspirated from all wells and replaced with fresh media containing 5 ⁇ Ci/mL 3 H-thymidine. Following a further 2 h 37° C.
- IC 50 values concentration of drug conjugate required to reduce 3 H-thymidine incorporation into newly synthesized DNA by 50%
- IC 50 values concentration of drug conjugate required to reduce 3 H-thymidine incorporation into newly synthesized DNA by 50%
- the cytotoxicities of these conjugates are reduced in the presence of excess free folic acid, indicating that the observed cell killing was mediated by binding to the folate receptor.
- mice Four to seven week-old mice (Balb/c or nu/nu strains) are purchased from Harlan Sprague Dawley, Inc. (Indianapolis, Ind.). Since normal rodent chow contains a high concentration of folic acid (6 mg/kg chow), mice used in these studies are maintained on the folate-free diet (Harlan diet #TD00434) for 1 week before tumor implantation to achieve serum folate concentrations close to the range of normal human serum. For tumor cell inoculation, 1 ⁇ 10 6 M109 cells or 1 ⁇ 10 6 KB cells in 100 ⁇ L are injected in the subcutis of the dorsal medial area.
- Log cell kill (LCK) and treated over control (T/C) values are then calculated according to published procedures (see, e.g., Lee et al., “BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy” Clin Cancer Res 7:1429-1437 (2001); Rose, “Taxol-based combination chemotherapy and other in vivo preclinical antitumor studies” J Natl Cancer Inst Monogr 47-53 (1993)).
- Dosing solutions are prepared fresh each day in PBS and administered through the lateral tail vein of the mice. Importantly, dosing is initiated when the s.c. tumors were between 50-100 mm 3 in volume.
- Persistent drug toxicity is assessed by collecting blood via cardiac puncture and submitting the serum for independent analysis of blood urea nitrogen (BUN), creatinine, total protein, AST-SGOT, ALT-SGPT plus a standard hematological cell panel at Ani-Lytics, Inc. (Gaithersburg, Md.).
- BUN blood urea nitrogen
- AST-SGOT creatinine
- ALT-SGPT ALT-SGPT plus a standard hematological cell panel at Ani-Lytics, Inc.
- histopathologic evaluation of formalin-fixed heart, lungs, liver, spleen, kidney, intestine, skeletal muscle and bone is conducted by board-certified pathologists at Animal Reference Pathology Laboratories (ARUP; Salt Lake City, Utah).
Abstract
Description
|
Factor | R1 | T |
A | (CH3)2CHCH2 | OH |
B | CH3(CH2)2 | OH |
C | CH3CH2 | OH |
D | (CH3)2CHCH2 | H |
E | CH3(CH2)2 | H |
F | CH2CH3 | H |
G | (CH3)2C═CH | OH |
H | CH3 | H |
I | CH3 | OH |
Two particular species of mycobacteria synthesize tubulysins in high titer during fermentation. However, each species generally synthesizes a mixture of tubulysin factors, and that mixture differs between each of those mycobacteria species. For example, one species, Archangium gephyra, produces as the main component factors tubulysins A, B, C, G, and I, each of which may be identified by its including the Tut residue. In contrast, another species, Angiococcus disciformis, produces as the main component factors tubulysins D, E, F, and H, each of which may be identified by its including the Tup residue.
wherein R, R1, S, T, U, V, W, Y, and Z are as described hereinbelow in the various embodiments, aspects, and variations thereof.
wherein R, R1, R10, S, T, U, V, W, Y, and Z are as described hereinbelow in the various embodiments, aspects, and variations thereof.
and pharmaceutical salts thereof, where R, R1, and R10 are as described in the various embodiments herein.
wherein R10 is H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted; V is H, OR2, or halo, and W is H, OR2, or alkyl, where R2 is independently selected in each instance from H, alkyl, or COR3, where R3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R2 is not H when both V and W are OR2; or V and W are taken together with the attached carbon to form a carbonyl; Z is CH3 or COR4, and Y is absent; or Z is CH3 and, Y is O; where R4 is alkyl, CF3 or aryl; T is H or OR6, where R6 is H, alkyl, aryl, COR7, P(O)(OR8)2, or SO3R8, where R7 and R8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R8 is a metal cation; and S and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy, or the corresponding carboxylic acid derivative thereof, where R is other than OH. The intermediate compound of formula (1b) is then treated with a compound of formula R10CO2H, where R10 is not the same as R10 in the first tubulysin to prepare the second compound of formula (2b).
wherein T is H or OH and R10 is H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or the corresponding carboxylic acid derivative thereof, where R is other than OH. The intermediate compound of formula (1c) is then treated with a compound of formula R10CO2H where R10 is not the same as R1 present in the starting tubulysin used to prepare the second compound of formula (2c).
wherein Q is —N—, —O—, or —S—; R9 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted, or R9 is C(O)R20, S(O)2R20, or P(O)(OR20)2; where R20 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R20 is a metal cation; V is H, OR2, or halo, and W is H, OR2, or alkyl, where R2 is independently selected in each instance from H, alkyl, or COR3, where R3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R2 is not H when both V and W are OR2; or V and W are taken together with the attached carbon to form a carbonyl Z is CH3 or COR4, and Y is absent; or Z is CH3 and, Y is O; where R4 is alkyl, CF3 or aryl; T is H or OR6, where R6 is H, alkyl, aryl, COR7, P(O)(OR8)2, or SO3R8, where R7 and R8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R8 is a metal cation; and S and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein Q is —N—, —O—, or —S—; R9 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted, or R9 is C(O)R20, S(O)2R20, or P(O)(OR20)2; where R20 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R20 is a metal cation: and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein R21 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted; V is H, OR2, or halo, and W is H, OR2, or alkyl, where R2 is independently selected in each instance from H, alkyl, or COR3, where R3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R2 is not H when both V and W are OR2; or V and W are taken together with the attached carbon to form a carbonyl Z is CH3 or COR4, and Y is absent; or Z is CH3 and, Y is O; where R4 is alkyl, CF3 or aryl; T is H or OR6, where R6 is H, alkyl, aryl, COR7, P(O)(OR8)2, or SO3R8, where R7 and R8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R8 is a metal cation; and S and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein R21 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein R22 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted; V is H, OR2, or halo, and W is H, OR2, or alkyl, where R2 is independently selected in each instance from H, alkyl, or COR3, where R3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R2 is not H when both V and W are OR2; or V and W are taken together with the attached carbon to form a carbonyl; Z is CH3 or COR4, and Y is absent; or Z is CH3 and, Y is O; where R4 is alkyl, CF3 or aryl; T is H or OR6, where R6 is H, alkyl, aryl, COR7, P(O)(OR8)2, or SO3R8, where R7 and R8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R8 is a metal cation; and S and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein R22 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein R23 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted; Ra is C(O)R9, C(O)OR9 or CN; R9 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted; V is H, OR2, or halo, and W is H, OR2, or alkyl, where R2 is independently selected in each instance from H, alkyl, or COR3, where R3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R2 is not H when both V and W are OR2; or V and W are taken together with the attached carbon to form a carbonyl; Z is CH3 or COR4, and Y is absent; or Z is CH3 and, Y is O; where R4 is alkyl, CF3 or aryl; T is H or OR6, where R6 is H, alkyl, aryl, COR7, P(O)(OR8)2, or SO3R8, where R7 and R8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R8 is a metal cation; and S and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein R23 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted; Ra is C(O)R9, C(O)OR9 or CN; R9 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted: and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein V is H, OR2, or halo, and W is H, OR2, or alkyl, where R2 is independently selected in each instance from H, alkyl, or COR3, where R3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R2 is not H when both V and W are OR2; or V and W are taken together with the attached carbon to form a carbonyl; Z is CH3 or COR4, and Y is absent; or Z is CH3 and, Y is O; where R4 is alkyl, CF3 or aryl; T is H or OR6, where R6 is H, alkyl, aryl, COR7, P(O)(OR8)2, or SO3R8, where R7 and R8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R8 is a metal cation; and S and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein X3 is halogen, OS(O)2R24, OP(O)(OR24)R24, or OP(O)(OR24)2; where R24 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R24 is a metal cation; V is H, OR2, or halo, and W is H, OR2, or alkyl, where R2 is independently selected in each instance from H, alkyl, or COR3, where R3 is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, each of which is optionally substituted, providing that R2 is not H when both V and W are OR2; or V and W are taken together with the attached carbon to form a carbonyl; Z is CH3 or COR4, and Y is absent; or Z is CH3 and, Y is O; where R4 is alkyl, CF3 or aryl; T is H or OR6, where R6 is H, alkyl, aryl, COR7, P(O)(OR8)2, or SO3R8, where R7 and R8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R8 is a metal cation; and S and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein X3 is halogen, OS(O)2R24, OP(O)(OR24)R24, or OP(O)(OR24)2; where R24 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R24 is a metal cation; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
is described, wherein R10 is H, alkyl, cycloalkyl, alkenyl, aryl or arylalkyl, each of which is optionally substituted: and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH; is treated with trifluoroacetic acid and the mixture is concentrated under reduced pressure to give an intermediate iminium compound. It is understood that such iminium compounds may be present as the corresponding trifluoroacetate salt compounds, and other hydrates and solvates, and as the acylaminal compound, and other addition adducts, as is illustrated by the following formulae:
Mixing the compound of those formulae, or other corresponding intermediates described herein and prepared by treatment of compound (2d) with TFA, and with an alcohol gives the corresponding N,O-acetal compound of the following formula:
wherein R9 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted, or R9 is C(O)R20, S(O)2R20, or P(O)(OR20)2; where R20 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R20 is a metal cation: and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein R9 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted, or R9 is C(O)R20, S(O)2R20, or P(O)(OR20)2; where R20 is independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R20 is a metal cation: and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein R21 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein R23 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted; Ra is C(O)R8, C(O)OR8 or CN; R8 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein R22 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
which may also be referred to as hydroxytubulysin D when T is OH, or hydroxytubulysin A when T is OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein R24 is alkyl, cycloalkyl, alkenyl, aryl or arylalkyl, each of which is optionally substituted; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
wherein X4 is Br or I; and T is H or OH, or the corresponding carboxylic acid derivative thereof, where R is other than OH.
and pharmaceutical salts thereof, where n is 1-3; T is H or OR6, where R6 is H, alkyl, aryl, COR7, P(O)(OR8)2, or SO3R8, where R7 and R8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R8 is a metal cation, or R6 is a phenol protecting group, or a prodrug moiety; Z is alkyl or C(O)R4, where R4 is alkyl, CF3, or aryl; and R is OH or a leaving group, or R forms a carboxylic acid derivative. Illustrative examples of such compounds, and their preparation are described in J. Med. Chem. 51, 1530-1533 (2008), the disclosure of which is incorporated herein by reference. It is understood that the conjugates may be formed at any heteroatom in the foregoing formula by removing the corresponding hydrogen or other group, including but not limited to conjugates formed by removing the hydrogen from R when R=OH, from T when T=OH, and the like. Conjugates described herein may include spacer linkers and/or releasable linkers as generally described in US Patent Application Publication 2005/0002942, the disclosure of which is incorporated herein by reference. In addition, conjugates described herein may include targeting ligands, including but not limited to folate and analogs and derivatives of folate, for targeting the conjugates to pathogenic cell populations, such as generally described in US Patent Application Publication 2005/0002942.
and pharmaceutical salts thereof, where n is 1-3; T is H or OR6, where R6 is H, alkyl, aryl, COR7, P(O)(OR8)2, or SO3R8, where R7 and R8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R8 is a metal cation, or R6 is a phenol protecting group, or a prodrug moiety; Z is alkyl or C(O)R4, where R4 is alkyl, CF3, or aryl; and R is OH or a leaving group, or R forms a carboxylic acid derivative. Illustrative examples of such compounds, and their preparation are described in J. Med. Chem. 51, 1530-1533 (2008), the disclosure of which is incorporated herein by reference.
and pharmaceutical salts thereof, where n, S, T, U, V, W, Z, R, and R10 are as described in the various embodiments herein.
and pharmaceutical salts thereof, where n, S, T, U, V, W, Z, QR9, and R are as described in the various embodiments herein. In one variation, Q is —N—, —O—, or —S—; and R9 is H, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted. In another variation, QR9 are taken together to form C(O)R10, S(O)2R10, P(O)(OR10a)2, where R10 and OR10a are independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R10a is a metal cation.
and pharmaceutical salts thereof, where R12 represents 1 or more substituents selected from alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted; and where n, S, T, U, V, W, Z, and R are as described in the various embodiments herein. It is to be understood that other olefins may form by isomerization, depending on the conditions of the reaction and the identity of R1. For example, when R1 is alkyl, it is appreciated that under the reaction conditions, the double bond can migrate to other carbon atoms along the alkenyl chain, including to form the terminal or ω-olefin.
and pharmaceutical salts thereof, where R13 is C(O)R10, C(O)OR10 or CN; and where n, S, T, U, V, W, Z, R, and R10 are as described in the various embodiments herein, where R10 is independently selected in each instance.
and pharmaceutical salts thereof, where n, S, T, U, V, W, Z, and R are as described in the various embodiments herein.
and pharmaceutical salts thereof, where X3 is halogen, OS(O)2R10, OP(O)(OR10a)R10, or OP(O)(OR10a)2; where R10 and R10a are independently selected in each instance from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R10a is a metal cation; and where n, S, T, U, V, W, Z, and R are as described in the various embodiments herein.
The 1H NMR spectrum of hydroxytubulysin A was consistent with the structure; the MS had an m/z=760. The 1H NMR spectrum of tubulysin B obtained in this experiment was consistent with the structure; the MS had an m/z=830.
Example | Cytotoxicity IC50 (nM) | ||
Tubulysin A | 2 | ||
Tubulysin B | 2.6 | ||
EC0313 | 9 | ||
EC0346 | 18 | ||
EC0550 | 2 | ||
EC0356 | 12 | ||
EC0374 | 24 | ||
EC0585 | 8 | ||
EC0386 | 42 | ||
EC0623 | 0.48 | ||
EC0346 | 18 | ||
Claims (29)
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160016993A1 (en) * | 2013-03-01 | 2016-01-21 | Endocyte, Inc. | Process for preparing tubulysins |
US9745341B2 (en) | 2007-10-25 | 2017-08-29 | Endocyte, Inc. | Tubulysins and processes for preparing |
Families Citing this family (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006012527A1 (en) | 2004-07-23 | 2006-02-02 | Endocyte, Inc. | Bivalent linkers and conjugates thereof |
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US9951324B2 (en) | 2010-02-25 | 2018-04-24 | Purdue Research Foundation | PSMA binding ligand-linker conjugates and methods for using |
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US10080805B2 (en) | 2012-02-24 | 2018-09-25 | Purdue Research Foundation | Cholecystokinin B receptor targeting for imaging and therapy |
US20140080175A1 (en) * | 2012-03-29 | 2014-03-20 | Endocyte, Inc. | Processes for preparing tubulysin derivatives and conjugates thereof |
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GB202117928D0 (en) | 2021-12-11 | 2022-01-26 | Cancer Research Tech Ltd | Immunotherapy for cancer |
WO2023169896A1 (en) | 2022-03-09 | 2023-09-14 | Astrazeneca Ab | BINDING MOLECULES AGAINST FRα |
Citations (109)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2515483A (en) | 1946-08-10 | 1950-07-18 | Merck & Co Inc | Diacylated pteroic acid and process for preparing same |
US2816110A (en) | 1956-11-23 | 1957-12-10 | Merck & Co Inc | Methods for the production of substituted pteridines |
US3387001A (en) | 1964-10-19 | 1968-06-04 | Lilly Co Eli | Novel aminoacyl esters of desacetyl vincaleukoblastine |
US3392173A (en) | 1964-03-09 | 1968-07-09 | Lilly Co Eli | Novel acyl derivatives of desacetyl-vincaleukoblastine and processes for their preparation |
US4166810A (en) | 1978-04-20 | 1979-09-04 | Eli Lilly And Company | Derivatives of 4-desacetyl VLB C-3 carboxyhydrazide |
US4203898A (en) | 1977-08-29 | 1980-05-20 | Eli Lilly And Company | Amide derivatives of VLB, leurosidine, leurocristine and related dimeric alkaloids |
US4337339A (en) | 1979-04-30 | 1982-06-29 | Baker Instruments Corp. | Process for preparation of folic acid derivatives |
EP0116208A1 (en) | 1982-12-07 | 1984-08-22 | Kyowa Hakko Kogyo Co., Ltd. | Mitomycin analogues |
JPS59175493A (en) | 1983-03-25 | 1984-10-04 | Kyowa Hakko Kogyo Co Ltd | Mitomycin derivative and its preparation |
JPS60255789A (en) | 1984-06-01 | 1985-12-17 | Kyowa Hakko Kogyo Co Ltd | Mitomycin derivative, its preparation, and antitumor agent |
US4713249A (en) | 1981-11-12 | 1987-12-15 | Schroeder Ulf | Crystallized carbohydrate matrix for biologically active substances, a process of preparing said matrix, and the use thereof |
WO1988001622A1 (en) | 1986-08-29 | 1988-03-10 | Kyowa Hakko Kogyo Kabusiki Kaisha | Mitomycin derivatives |
US4801688A (en) | 1986-05-27 | 1989-01-31 | Eli Lilly And Company | Hydrazone immunoglobulin conjugates |
US4866180A (en) | 1984-02-24 | 1989-09-12 | Bristol-Myers Company | Amino disulfide thiol exchange products |
EP0354728A2 (en) | 1988-08-08 | 1990-02-14 | Eli Lilly And Company | Cytotoxic drug conjugates |
WO1990012096A1 (en) | 1989-04-03 | 1990-10-18 | Purdue Research Foundation | Method for enhancing transmembrane transport of exogenous molecules |
WO1991007418A1 (en) | 1989-11-13 | 1991-05-30 | Xoma Corporation | Chimeric mouse-human a10 antibody with specificity to a human tumor cell antigen |
US5094849A (en) | 1988-08-08 | 1992-03-10 | Eli Lilly And Company | Cytotoxic antibody conjugates of hydrazide derivatized vinca analogs via simple organic linkers |
US5140104A (en) | 1982-03-09 | 1992-08-18 | Cytogen Corporation | Amine derivatives of folic acid analogs |
US5266333A (en) | 1985-03-06 | 1993-11-30 | American Cyanamid Company | Water dispersible and water soluble carbohydrate polymer compositions for parenteral administration of growth hormone |
US5417982A (en) | 1994-02-17 | 1995-05-23 | Modi; Pankaj | Controlled release of drugs or hormones in biodegradable polymer microspheres |
US5547668A (en) | 1995-05-05 | 1996-08-20 | The Board Of Trustees Of The University Of Illinois | Conjugates of folate anti-effector cell antibodies |
US5552545A (en) | 1991-12-20 | 1996-09-03 | Eli Lilly And Company | 5-deaza-10-oxo-and 5-deaza-10-thio-5,6,7,8-tetrahydrofolic acids |
WO1996036367A1 (en) | 1995-05-16 | 1996-11-21 | Purdue Research Foundation | Composition and method for tumor imaging |
US5627165A (en) | 1990-06-13 | 1997-05-06 | Drug Innovation & Design, Inc. | Phosphorous prodrugs and therapeutic delivery systems using same |
US5672486A (en) | 1990-08-29 | 1997-09-30 | Centre Hospitalier Regional De Nantes | Protein polyligands joined to a stable protein core |
WO1998010651A1 (en) | 1996-09-12 | 1998-03-19 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
WO1999020626A1 (en) | 1997-10-17 | 1999-04-29 | Purdue Research Foundation | Folic acid derivatives |
WO1999061055A1 (en) | 1998-05-22 | 1999-12-02 | The Board Of Trustees Of The Leland Stanford Junior University | Bifunctional molecules and therapies based thereon |
US5998603A (en) | 1994-09-29 | 1999-12-07 | Isis Pharmaceuticals, Inc. | 4'-desmethyl nucleoside analogs, and oligomers thereof |
US6004555A (en) | 1992-03-05 | 1999-12-21 | Board Of Regents, The University Of Texas System | Methods for the specific coagulation of vasculature |
US6030941A (en) | 1996-05-01 | 2000-02-29 | Avi Biopharma, Inc. | Polymer composition for delivering substances in living organisms |
US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
US6077499A (en) | 1996-05-03 | 2000-06-20 | Immunomedics, Inc. | Targeted combination immunotherapy of cancer |
US6093382A (en) | 1998-05-16 | 2000-07-25 | Bracco Research Usa Inc. | Metal complexes derivatized with folate for use in diagnostic and therapeutic applications |
WO2000035422A3 (en) | 1998-12-18 | 2000-10-12 | Hadasit Med Res Service | Method of administering a compound to multi-drug resistant cells |
WO2000066091A1 (en) | 1999-05-04 | 2000-11-09 | Biotech Australia Pty Limited | Amplification of folate-mediated targeting to tumor cells using polymers |
CA2376175A1 (en) | 1999-06-02 | 2000-12-14 | Biotech Australia Pty Limited | Vitamin directed dual targeting therapy |
US6171614B1 (en) | 1996-10-15 | 2001-01-09 | Emory University | Synthesis of glycophospholipid and peptide-phospholipid conjugates and uses thereof |
US6171859B1 (en) | 1994-03-30 | 2001-01-09 | Mitokor | Method of targeting conjugate molecules to mitochondria |
US6177404B1 (en) | 1996-10-15 | 2001-01-23 | Merck & Co., Inc. | Conjugates useful in the treatment of benign prostatic hyperplasia |
US6184042B1 (en) | 1996-05-24 | 2001-02-06 | Boehringer Mannheim Gmbh | Method for reducing hook effect in an immunoassay |
US6207157B1 (en) | 1996-04-23 | 2001-03-27 | The United States Of America As Represented By The Department Of Health And Human Services | Conjugate vaccine for nontypeable Haemophilus influenzae |
WO2001028592A1 (en) | 1999-10-15 | 2001-04-26 | Mayo Foundation For Medical Education And Research | Cobalamin conjugates useful as imaging agents and as antitumor agents |
US6291684B1 (en) | 1999-03-29 | 2001-09-18 | Bristol-Myers Squibb Company | Process for the preparation of aziridinyl epothilones from oxiranyl epothilones |
US6335434B1 (en) | 1998-06-16 | 2002-01-01 | Isis Pharmaceuticals, Inc., | Nucleosidic and non-nucleosidic folate conjugates |
US6365179B1 (en) | 1999-04-23 | 2002-04-02 | Alza Corporation | Conjugate having a cleavable linkage for use in a liposome |
US6399625B1 (en) | 2000-09-27 | 2002-06-04 | Wyeth | 1-oxorapamycins |
US6399626B1 (en) | 2000-10-02 | 2002-06-04 | Wyeth | Hydroxyesters of 7-desmethylrapamycin |
US6399638B1 (en) | 1998-04-21 | 2002-06-04 | Bristol-Myers Squibb Company | 12,13-modified epothilone derivatives |
US6432973B1 (en) | 2000-09-19 | 2002-08-13 | Wyeth | Water soluble rapamycin esters |
US6440991B1 (en) | 2000-10-02 | 2002-08-27 | Wyeth | Ethers of 7-desmethlrapamycin |
WO2001074382A9 (en) | 2000-03-31 | 2002-10-10 | Purdue Research Foundation | Method of treatment using ligand-immunogen conjugates |
WO2002085908A1 (en) | 2001-04-24 | 2002-10-31 | Purdue Research Foundation | Folate mimetics and folate-receptor binding conjugates thereof |
WO2002098868A1 (en) | 2001-06-01 | 2002-12-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
US6511986B2 (en) | 2000-08-11 | 2003-01-28 | Wyeth | Method of treating estrogen receptor positive carcinoma |
WO2002087424A3 (en) | 2001-05-02 | 2003-03-20 | Philip Stewart Low | Treatment and diagnosis of macrophage mediated disease |
US6541612B2 (en) | 1993-04-23 | 2003-04-01 | Wyeth | Monoclonal antibodies obtained using rapamycin position 27 conjugates as an immunogen |
US20030086900A1 (en) | 2001-09-28 | 2003-05-08 | Low Philip S. | Method of treatment using ligand-immunogen conjugates |
US6596757B1 (en) | 2002-05-14 | 2003-07-22 | Immunogen Inc. | Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use |
US20030162234A1 (en) | 2002-02-07 | 2003-08-28 | Jallad Karim N. | Folate targeted enhanced tumor and folate receptor positive tissue optical imaging technology |
US6617333B2 (en) | 2001-08-07 | 2003-09-09 | Wyeth | Antineoplastic combinations comprising |
WO2003097647A1 (en) | 2002-05-15 | 2003-11-27 | Endocyte, Inc. | Vitamin-mitomycin conjugates |
US6670355B2 (en) | 2000-06-16 | 2003-12-30 | Wyeth | Method of treating cardiovascular disease |
US6677357B2 (en) | 2001-08-22 | 2004-01-13 | Wyeth | Rapamycin 29-enols |
WO2004005327A1 (en) | 2002-07-09 | 2004-01-15 | Morphochem Ag Komb Chemie | Novel tubulysin analogues |
US6680330B2 (en) | 2001-08-22 | 2004-01-20 | Wyeth | Rapamycin dialdehydes |
US20040018203A1 (en) | 2001-06-08 | 2004-01-29 | Ira Pastan | Pegylation of linkers improves antitumor activity and reduces toxicity of immunoconjugates |
WO2004005326A3 (en) | 2002-07-09 | 2004-02-19 | Morphochem Aktiengellschaft Fu | Tubulysin conjugates |
US20040033195A1 (en) | 2002-05-06 | 2004-02-19 | Leamon Christopher P. | Vitamin-targeted imaging agents |
US6713607B2 (en) | 1994-03-08 | 2004-03-30 | Wyeth | Effector proteins of Rapamycin |
WO2004012735A3 (en) | 2002-07-31 | 2004-05-27 | Schering Ag | New effector conjugates, process for their production and their pharmaceutical use |
WO2004054622A1 (en) | 2002-12-13 | 2004-07-01 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
WO2004046170A3 (en) | 2002-11-21 | 2004-07-01 | Biotechnolog Forschung Gmbh | Tubulysins, method for producing the same and tubulysin preparations |
US6821731B2 (en) | 2000-11-28 | 2004-11-23 | Wyeth | Expression analysis of FKBP nucleic acids and polypeptides useful in the diagnosis of prostate cancer |
US20050002942A1 (en) | 2003-01-27 | 2005-01-06 | Vlahov Iontcho R. | Vitamin receptor binding drug delivery conjugates |
US20050026068A1 (en) | 2001-11-01 | 2005-02-03 | Evangelos Gogolides | Polycarbocyclic derivatives for modification of resist, optical and etch resistance properties |
US20050107325A1 (en) | 2003-04-17 | 2005-05-19 | Muthiah Manoharan | Modified iRNA agents |
US6915855B2 (en) | 2002-05-02 | 2005-07-12 | Halliburton Energy Services, Inc. | Wellbore junction drifting apparatus and associated method |
US6958153B1 (en) | 1997-11-07 | 2005-10-25 | Wyeth | Skin penetration enhancing components |
US20050239739A1 (en) | 2001-05-18 | 2005-10-27 | Sirna Therapeutics, Inc. | Conjugates and compositions for cellular delivery |
WO2004100983A3 (en) | 2003-05-06 | 2005-11-10 | Purdue Res Foundation Inc | Treatment of lupus targeting the macrophages or the folate receptor |
WO2006012527A8 (en) | 2004-07-23 | 2006-03-09 | Endocyte Inc | Bivalent linkers and conjugates thereof |
US20060058266A1 (en) | 2004-08-10 | 2006-03-16 | Muthiah Manoharan | Chemically modified oligonucleotides |
US7019014B2 (en) | 2003-05-12 | 2006-03-28 | Wyeth Holdings Corporation | Process for producing anticancer agent LL-D45042 |
WO2005074901A3 (en) | 2004-01-30 | 2006-03-30 | Schering Ag | New effector conjugates, process for their production and their pharmaceutical use |
US7029674B2 (en) | 2001-04-02 | 2006-04-18 | Wyeth | Methods for downmodulating immune cells using an antibody to PD-1 |
WO2006042146A2 (en) | 2004-10-07 | 2006-04-20 | Emory University | Multifunctional nanoparticles conjugates and their use |
US7060797B2 (en) | 2002-11-21 | 2006-06-13 | Wyeth | Composition and method for treating lupus nephritis |
US7060709B2 (en) | 2003-02-06 | 2006-06-13 | Wyeth | Method of treating hepatic fibrosis |
US7067111B1 (en) | 1999-10-25 | 2006-06-27 | Board Of Regents, University Of Texas System | Ethylenedicysteine (EC)-drug conjugates, compositions and methods for tissue specific disease imaging |
US7074804B2 (en) | 2003-07-16 | 2006-07-11 | Wyeth | CCI-779 Isomer C |
US7105328B2 (en) | 2001-04-02 | 2006-09-12 | Dana-Farber Cancer Institute | Methods for screening for compounds that modulate pd-1 signaling |
WO2006105141A1 (en) | 2005-03-30 | 2006-10-05 | Purdue Research Foundation | Method for cancer prognosis using cellular folate vitamin receptor quantification |
US7122361B2 (en) | 2002-10-10 | 2006-10-17 | Wyeth | Compositions employing a novel human kinase |
WO2005112919A8 (en) | 2004-05-19 | 2006-12-07 | Medarex Inc | Self-immolative linkers and drug conjugates |
US7153957B2 (en) | 2003-08-07 | 2006-12-26 | Wyeth | Regioselective synthesis of CCI-779 |
US20070009434A1 (en) | 2005-07-05 | 2007-01-11 | Low Philip S | Imaging and therapeutic method using monocytes |
WO2006101845A3 (en) | 2005-03-16 | 2007-03-29 | Endocyte Inc | Synthesis and purification of pteroic acid and conjugates thereof |
WO2007022494A3 (en) | 2005-08-19 | 2007-09-07 | Endocyte Inc | Multi-drug ligand conjugates |
US20070275904A1 (en) | 2006-05-25 | 2007-11-29 | Bristol-Myers Squibb Company | Conjugates of aziridinyl-epothilone analogs and pharmaceutical compositions comprising same |
WO2007022493A3 (en) | 2005-08-19 | 2008-01-24 | Endocyte Inc | Ligand conjugates of vinca alkaloids, analogs, and derivatives |
WO2008101231A2 (en) | 2007-02-16 | 2008-08-21 | Endocyte, Inc. | Methods and compositions for treating and diagnosing kidney disease |
WO2009002993A1 (en) | 2007-06-25 | 2008-12-31 | Endocyte, Inc. | Conjugates containing hydrophilic spacer linkers |
WO2009055562A1 (en) | 2007-10-25 | 2009-04-30 | Endocyte, Inc. | Tubulysins and processes for preparing |
WO2008112873A3 (en) | 2007-03-14 | 2009-09-11 | Endocyte, Inc. | Binding ligand linked drug delivery conjugates of tubulysins |
WO2011069116A1 (en) | 2009-12-04 | 2011-06-09 | Endocyte, Inc. | Binding ligand linked drug delivery conjugates of tubulysins |
WO2011106639A1 (en) | 2010-02-25 | 2011-09-01 | Purdue Research Foundation | Psma binding ligand-linker conjugates and methods for using |
WO2012019123A1 (en) | 2010-08-06 | 2012-02-09 | Endocyte, Inc. | Processes for preparing tubulysins |
-
2008
- 2008-10-23 EP EP08841521.1A patent/EP2209374B1/en not_active Not-in-force
- 2008-10-23 US US12/739,579 patent/US9187521B2/en not_active Expired - Fee Related
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- 2008-10-23 WO PCT/US2008/080948 patent/WO2009055562A1/en active Application Filing
- 2008-10-23 JP JP2010531240A patent/JP2011500835A/en active Pending
- 2008-10-23 CA CA2703491A patent/CA2703491C/en not_active Expired - Fee Related
- 2008-10-23 CN CN200880123654.6A patent/CN101909441B/en not_active Expired - Fee Related
-
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- 2010-04-22 IL IL205253A patent/IL205253A/en not_active IP Right Cessation
-
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- 2014-06-18 JP JP2014125594A patent/JP6077493B2/en not_active Expired - Fee Related
-
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- 2015-10-23 US US14/921,196 patent/US9745341B2/en not_active Expired - Fee Related
-
2016
- 2016-10-14 JP JP2016203012A patent/JP2017061469A/en active Pending
Patent Citations (140)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2515483A (en) | 1946-08-10 | 1950-07-18 | Merck & Co Inc | Diacylated pteroic acid and process for preparing same |
US2816110A (en) | 1956-11-23 | 1957-12-10 | Merck & Co Inc | Methods for the production of substituted pteridines |
US3392173A (en) | 1964-03-09 | 1968-07-09 | Lilly Co Eli | Novel acyl derivatives of desacetyl-vincaleukoblastine and processes for their preparation |
US3387001A (en) | 1964-10-19 | 1968-06-04 | Lilly Co Eli | Novel aminoacyl esters of desacetyl vincaleukoblastine |
US4203898A (en) | 1977-08-29 | 1980-05-20 | Eli Lilly And Company | Amide derivatives of VLB, leurosidine, leurocristine and related dimeric alkaloids |
US4166810A (en) | 1978-04-20 | 1979-09-04 | Eli Lilly And Company | Derivatives of 4-desacetyl VLB C-3 carboxyhydrazide |
US4337339A (en) | 1979-04-30 | 1982-06-29 | Baker Instruments Corp. | Process for preparation of folic acid derivatives |
US4713249A (en) | 1981-11-12 | 1987-12-15 | Schroeder Ulf | Crystallized carbohydrate matrix for biologically active substances, a process of preparing said matrix, and the use thereof |
US5140104A (en) | 1982-03-09 | 1992-08-18 | Cytogen Corporation | Amine derivatives of folic acid analogs |
EP0116208A1 (en) | 1982-12-07 | 1984-08-22 | Kyowa Hakko Kogyo Co., Ltd. | Mitomycin analogues |
JPS59175493A (en) | 1983-03-25 | 1984-10-04 | Kyowa Hakko Kogyo Co Ltd | Mitomycin derivative and its preparation |
US4866180A (en) | 1984-02-24 | 1989-09-12 | Bristol-Myers Company | Amino disulfide thiol exchange products |
US4691024A (en) | 1984-06-01 | 1987-09-01 | Kyowa Hakko Kogyo Kabushiki Kaisha | New mitomycin derivatives, preparation thereof and pharmaceutical compositions containing them |
JPS60255789A (en) | 1984-06-01 | 1985-12-17 | Kyowa Hakko Kogyo Co Ltd | Mitomycin derivative, its preparation, and antitumor agent |
US5266333A (en) | 1985-03-06 | 1993-11-30 | American Cyanamid Company | Water dispersible and water soluble carbohydrate polymer compositions for parenteral administration of growth hormone |
US4801688A (en) | 1986-05-27 | 1989-01-31 | Eli Lilly And Company | Hydrazone immunoglobulin conjugates |
WO1988001622A1 (en) | 1986-08-29 | 1988-03-10 | Kyowa Hakko Kogyo Kabusiki Kaisha | Mitomycin derivatives |
EP0280741A1 (en) | 1986-08-29 | 1988-09-07 | Kyowa Hakko Kogyo Kabushiki Kaisha | Mitomycin derivatives |
EP0354728A2 (en) | 1988-08-08 | 1990-02-14 | Eli Lilly And Company | Cytotoxic drug conjugates |
US5094849A (en) | 1988-08-08 | 1992-03-10 | Eli Lilly And Company | Cytotoxic antibody conjugates of hydrazide derivatized vinca analogs via simple organic linkers |
US5006652A (en) | 1988-08-08 | 1991-04-09 | Eli Lilly And Company | Intermediates for antibody-vinca drug conjugates |
US5635382A (en) | 1989-04-03 | 1997-06-03 | Purdue Research Foundation | Method for enhancing transmembrane transport of exogenous molecules |
US5108921A (en) | 1989-04-03 | 1992-04-28 | Purdue Research Foundation | Method for enhanced transmembrane transport of exogenous molecules |
WO1990012096A1 (en) | 1989-04-03 | 1990-10-18 | Purdue Research Foundation | Method for enhancing transmembrane transport of exogenous molecules |
US5416016A (en) | 1989-04-03 | 1995-05-16 | Purdue Research Foundation | Method for enhancing transmembrane transport of exogenous molecules |
US5688488A (en) | 1989-04-03 | 1997-11-18 | Purdue Research Foundation | Composition and method for tumor imaging |
WO1991007418A1 (en) | 1989-11-13 | 1991-05-30 | Xoma Corporation | Chimeric mouse-human a10 antibody with specificity to a human tumor cell antigen |
US5627165A (en) | 1990-06-13 | 1997-05-06 | Drug Innovation & Design, Inc. | Phosphorous prodrugs and therapeutic delivery systems using same |
US5672486A (en) | 1990-08-29 | 1997-09-30 | Centre Hospitalier Regional De Nantes | Protein polyligands joined to a stable protein core |
US5552545A (en) | 1991-12-20 | 1996-09-03 | Eli Lilly And Company | 5-deaza-10-oxo-and 5-deaza-10-thio-5,6,7,8-tetrahydrofolic acids |
US6004555A (en) | 1992-03-05 | 1999-12-21 | Board Of Regents, The University Of Texas System | Methods for the specific coagulation of vasculature |
US6541612B2 (en) | 1993-04-23 | 2003-04-01 | Wyeth | Monoclonal antibodies obtained using rapamycin position 27 conjugates as an immunogen |
US5417982A (en) | 1994-02-17 | 1995-05-23 | Modi; Pankaj | Controlled release of drugs or hormones in biodegradable polymer microspheres |
US6713607B2 (en) | 1994-03-08 | 2004-03-30 | Wyeth | Effector proteins of Rapamycin |
US6171859B1 (en) | 1994-03-30 | 2001-01-09 | Mitokor | Method of targeting conjugate molecules to mitochondria |
US5998603A (en) | 1994-09-29 | 1999-12-07 | Isis Pharmaceuticals, Inc. | 4'-desmethyl nucleoside analogs, and oligomers thereof |
US5547668A (en) | 1995-05-05 | 1996-08-20 | The Board Of Trustees Of The University Of Illinois | Conjugates of folate anti-effector cell antibodies |
WO1996036367A1 (en) | 1995-05-16 | 1996-11-21 | Purdue Research Foundation | Composition and method for tumor imaging |
US6207157B1 (en) | 1996-04-23 | 2001-03-27 | The United States Of America As Represented By The Department Of Health And Human Services | Conjugate vaccine for nontypeable Haemophilus influenzae |
US6030941A (en) | 1996-05-01 | 2000-02-29 | Avi Biopharma, Inc. | Polymer composition for delivering substances in living organisms |
US6077499A (en) | 1996-05-03 | 2000-06-20 | Immunomedics, Inc. | Targeted combination immunotherapy of cancer |
US6184042B1 (en) | 1996-05-24 | 2001-02-06 | Boehringer Mannheim Gmbh | Method for reducing hook effect in an immunoassay |
WO1998010651A1 (en) | 1996-09-12 | 1998-03-19 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
US6171614B1 (en) | 1996-10-15 | 2001-01-09 | Emory University | Synthesis of glycophospholipid and peptide-phospholipid conjugates and uses thereof |
US6177404B1 (en) | 1996-10-15 | 2001-01-23 | Merck & Co., Inc. | Conjugates useful in the treatment of benign prostatic hyperplasia |
US6291673B1 (en) | 1997-10-17 | 2001-09-18 | Purdue Research Foundation | Folic acid derivatives |
WO1999020626A1 (en) | 1997-10-17 | 1999-04-29 | Purdue Research Foundation | Folic acid derivatives |
US6958153B1 (en) | 1997-11-07 | 2005-10-25 | Wyeth | Skin penetration enhancing components |
US6399638B1 (en) | 1998-04-21 | 2002-06-04 | Bristol-Myers Squibb Company | 12,13-modified epothilone derivatives |
US6093382A (en) | 1998-05-16 | 2000-07-25 | Bracco Research Usa Inc. | Metal complexes derivatized with folate for use in diagnostic and therapeutic applications |
WO1999061055A1 (en) | 1998-05-22 | 1999-12-02 | The Board Of Trustees Of The Leland Stanford Junior University | Bifunctional molecules and therapies based thereon |
US6335434B1 (en) | 1998-06-16 | 2002-01-01 | Isis Pharmaceuticals, Inc., | Nucleosidic and non-nucleosidic folate conjugates |
WO2000035422A3 (en) | 1998-12-18 | 2000-10-12 | Hadasit Med Res Service | Method of administering a compound to multi-drug resistant cells |
US6291684B1 (en) | 1999-03-29 | 2001-09-18 | Bristol-Myers Squibb Company | Process for the preparation of aziridinyl epothilones from oxiranyl epothilones |
US6365179B1 (en) | 1999-04-23 | 2002-04-02 | Alza Corporation | Conjugate having a cleavable linkage for use in a liposome |
WO2000066091A1 (en) | 1999-05-04 | 2000-11-09 | Biotech Australia Pty Limited | Amplification of folate-mediated targeting to tumor cells using polymers |
CA2372841A1 (en) | 1999-05-04 | 2000-11-09 | Gregory John Russell-Jones | Amplification of folate-mediated targeting to tumor cells using polymers |
CA2376175A1 (en) | 1999-06-02 | 2000-12-14 | Biotech Australia Pty Limited | Vitamin directed dual targeting therapy |
WO2000074721A1 (en) | 1999-06-02 | 2000-12-14 | Biotech Australia Pty Limited | Vitamin directed dual targeting therapy |
WO2001028592A1 (en) | 1999-10-15 | 2001-04-26 | Mayo Foundation For Medical Education And Research | Cobalamin conjugates useful as imaging agents and as antitumor agents |
US20050004010A1 (en) | 1999-10-15 | 2005-01-06 | Mayo Foundation For Medical Education | Cobalamin conjugates useful as imaging agents and as antitumor agents |
US7067111B1 (en) | 1999-10-25 | 2006-06-27 | Board Of Regents, University Of Texas System | Ethylenedicysteine (EC)-drug conjugates, compositions and methods for tissue specific disease imaging |
WO2001074382A9 (en) | 2000-03-31 | 2002-10-10 | Purdue Research Foundation | Method of treatment using ligand-immunogen conjugates |
US7033594B2 (en) | 2000-03-31 | 2006-04-25 | Purdue Research Foundation | Method of treatment using ligand-immunogen conjugates |
US6670355B2 (en) | 2000-06-16 | 2003-12-30 | Wyeth | Method of treating cardiovascular disease |
US6511986B2 (en) | 2000-08-11 | 2003-01-28 | Wyeth | Method of treating estrogen receptor positive carcinoma |
US6432973B1 (en) | 2000-09-19 | 2002-08-13 | Wyeth | Water soluble rapamycin esters |
US6399625B1 (en) | 2000-09-27 | 2002-06-04 | Wyeth | 1-oxorapamycins |
US6440991B1 (en) | 2000-10-02 | 2002-08-27 | Wyeth | Ethers of 7-desmethlrapamycin |
US6399626B1 (en) | 2000-10-02 | 2002-06-04 | Wyeth | Hydroxyesters of 7-desmethylrapamycin |
US6821731B2 (en) | 2000-11-28 | 2004-11-23 | Wyeth | Expression analysis of FKBP nucleic acids and polypeptides useful in the diagnosis of prostate cancer |
US7029674B2 (en) | 2001-04-02 | 2006-04-18 | Wyeth | Methods for downmodulating immune cells using an antibody to PD-1 |
US7105328B2 (en) | 2001-04-02 | 2006-09-12 | Dana-Farber Cancer Institute | Methods for screening for compounds that modulate pd-1 signaling |
US20040242582A1 (en) | 2001-04-24 | 2004-12-02 | Green Mark A | Folate mimetics and folate-receptor binding conjugates thereof |
US20050227985A9 (en) | 2001-04-24 | 2005-10-13 | Green Mark A | Folate mimetics and folate-receptor binding conjugates thereof |
WO2002085908A1 (en) | 2001-04-24 | 2002-10-31 | Purdue Research Foundation | Folate mimetics and folate-receptor binding conjugates thereof |
WO2002087424A3 (en) | 2001-05-02 | 2003-03-20 | Philip Stewart Low | Treatment and diagnosis of macrophage mediated disease |
US20050239739A1 (en) | 2001-05-18 | 2005-10-27 | Sirna Therapeutics, Inc. | Conjugates and compositions for cellular delivery |
WO2002098868A1 (en) | 2001-06-01 | 2002-12-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
US6800653B2 (en) | 2001-06-01 | 2004-10-05 | Bristol-Myers Squibb Compnay | Epothilone derivatives |
US20040018203A1 (en) | 2001-06-08 | 2004-01-29 | Ira Pastan | Pegylation of linkers improves antitumor activity and reduces toxicity of immunoconjugates |
US6617333B2 (en) | 2001-08-07 | 2003-09-09 | Wyeth | Antineoplastic combinations comprising |
US6680330B2 (en) | 2001-08-22 | 2004-01-20 | Wyeth | Rapamycin dialdehydes |
US6677357B2 (en) | 2001-08-22 | 2004-01-13 | Wyeth | Rapamycin 29-enols |
US20030086900A1 (en) | 2001-09-28 | 2003-05-08 | Low Philip S. | Method of treatment using ligand-immunogen conjugates |
US20050026068A1 (en) | 2001-11-01 | 2005-02-03 | Evangelos Gogolides | Polycarbocyclic derivatives for modification of resist, optical and etch resistance properties |
US20030162234A1 (en) | 2002-02-07 | 2003-08-28 | Jallad Karim N. | Folate targeted enhanced tumor and folate receptor positive tissue optical imaging technology |
US6915855B2 (en) | 2002-05-02 | 2005-07-12 | Halliburton Energy Services, Inc. | Wellbore junction drifting apparatus and associated method |
US7128893B2 (en) | 2002-05-06 | 2006-10-31 | Endocyte, Inc. | Vitamin-targeted imaging agents |
US20040033195A1 (en) | 2002-05-06 | 2004-02-19 | Leamon Christopher P. | Vitamin-targeted imaging agents |
US6596757B1 (en) | 2002-05-14 | 2003-07-22 | Immunogen Inc. | Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use |
WO2003097647A1 (en) | 2002-05-15 | 2003-11-27 | Endocyte, Inc. | Vitamin-mitomycin conjugates |
US20050165227A1 (en) | 2002-05-15 | 2005-07-28 | Vlahov Iontcho R. | Vitamin-mitomycin conjugates |
US7816377B2 (en) | 2002-07-09 | 2010-10-19 | R&D-Biopharmaceuticals Gmbh | Tubulysin analogues |
WO2004005327A1 (en) | 2002-07-09 | 2004-01-15 | Morphochem Ag Komb Chemie | Novel tubulysin analogues |
WO2004005326A3 (en) | 2002-07-09 | 2004-02-19 | Morphochem Aktiengellschaft Fu | Tubulysin conjugates |
US20050239713A1 (en) | 2002-07-09 | 2005-10-27 | R&D-Biopharmaceuticals Am | Novel tubulysin analogues |
US7776814B2 (en) | 2002-07-09 | 2010-08-17 | R&D-Biopharmaceuticals Gmbh | Tubulysin conjugates |
WO2004012735A3 (en) | 2002-07-31 | 2004-05-27 | Schering Ag | New effector conjugates, process for their production and their pharmaceutical use |
US7122361B2 (en) | 2002-10-10 | 2006-10-17 | Wyeth | Compositions employing a novel human kinase |
US20060128754A1 (en) * | 2002-11-21 | 2006-06-15 | Gerhard Hoefle | Tubulysins, method for producing the same and tubulysin preparations |
US7060797B2 (en) | 2002-11-21 | 2006-06-13 | Wyeth | Composition and method for treating lupus nephritis |
WO2004046170A3 (en) | 2002-11-21 | 2004-07-01 | Biotechnolog Forschung Gmbh | Tubulysins, method for producing the same and tubulysin preparations |
US7754885B2 (en) | 2002-11-21 | 2010-07-13 | Helmholtz-Zentrum Fuer Infektionsforschung Gmbh | Tubulysins, method for producing the same and tubulysin preparations |
WO2004054622A1 (en) | 2002-12-13 | 2004-07-01 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
WO2004069159A3 (en) | 2003-01-27 | 2005-06-16 | Endocyte Inc | Vitamin receptor binding drug delivery conjugates |
US20050002942A1 (en) | 2003-01-27 | 2005-01-06 | Vlahov Iontcho R. | Vitamin receptor binding drug delivery conjugates |
US20100004276A1 (en) | 2003-01-27 | 2010-01-07 | Vlahov Iontcho R | Vitamin receptor binding drug delivery conjugates |
US7601332B2 (en) | 2003-01-27 | 2009-10-13 | Endocyte, Inc. | Vitamin receptor binding drug delivery conjugates |
US7060709B2 (en) | 2003-02-06 | 2006-06-13 | Wyeth | Method of treating hepatic fibrosis |
US20050107325A1 (en) | 2003-04-17 | 2005-05-19 | Muthiah Manoharan | Modified iRNA agents |
WO2004100983A3 (en) | 2003-05-06 | 2005-11-10 | Purdue Res Foundation Inc | Treatment of lupus targeting the macrophages or the folate receptor |
US7019014B2 (en) | 2003-05-12 | 2006-03-28 | Wyeth Holdings Corporation | Process for producing anticancer agent LL-D45042 |
US7074804B2 (en) | 2003-07-16 | 2006-07-11 | Wyeth | CCI-779 Isomer C |
US7153957B2 (en) | 2003-08-07 | 2006-12-26 | Wyeth | Regioselective synthesis of CCI-779 |
WO2005074901A3 (en) | 2004-01-30 | 2006-03-30 | Schering Ag | New effector conjugates, process for their production and their pharmaceutical use |
WO2005112919A8 (en) | 2004-05-19 | 2006-12-07 | Medarex Inc | Self-immolative linkers and drug conjugates |
WO2006012527A8 (en) | 2004-07-23 | 2006-03-09 | Endocyte Inc | Bivalent linkers and conjugates thereof |
US20090203889A1 (en) | 2004-07-23 | 2009-08-13 | Endocyte, Inc. | Bivalent linkers and conjugates thereof |
US20060058266A1 (en) | 2004-08-10 | 2006-03-16 | Muthiah Manoharan | Chemically modified oligonucleotides |
WO2006042146A2 (en) | 2004-10-07 | 2006-04-20 | Emory University | Multifunctional nanoparticles conjugates and their use |
WO2006101845A3 (en) | 2005-03-16 | 2007-03-29 | Endocyte Inc | Synthesis and purification of pteroic acid and conjugates thereof |
US20080207625A1 (en) | 2005-03-16 | 2008-08-28 | Endocyte, Inc. | Synthesis and Purification of Pteroic Acid and Conjugates Thereof |
WO2006105141A1 (en) | 2005-03-30 | 2006-10-05 | Purdue Research Foundation | Method for cancer prognosis using cellular folate vitamin receptor quantification |
US20070009434A1 (en) | 2005-07-05 | 2007-01-11 | Low Philip S | Imaging and therapeutic method using monocytes |
WO2007022493A3 (en) | 2005-08-19 | 2008-01-24 | Endocyte Inc | Ligand conjugates of vinca alkaloids, analogs, and derivatives |
US20080280937A1 (en) | 2005-08-19 | 2008-11-13 | Christopher Paul Leamon | Ligand Conjugates of Vinca Alkaloids, Analogs, and Derivatives |
US20080248052A1 (en) | 2005-08-19 | 2008-10-09 | Iontcho Radoslavov Vlahov | Multi-Drug Ligand Conjugates |
WO2007022494A3 (en) | 2005-08-19 | 2007-09-07 | Endocyte Inc | Multi-drug ligand conjugates |
US20070275904A1 (en) | 2006-05-25 | 2007-11-29 | Bristol-Myers Squibb Company | Conjugates of aziridinyl-epothilone analogs and pharmaceutical compositions comprising same |
WO2008101231A2 (en) | 2007-02-16 | 2008-08-21 | Endocyte, Inc. | Methods and compositions for treating and diagnosing kidney disease |
US20100104626A1 (en) | 2007-02-16 | 2010-04-29 | Endocyte, Inc. | Methods and compositions for treating and diagnosing kidney disease |
US20100048490A1 (en) | 2007-03-14 | 2010-02-25 | Iontcho Radoslavov Vlahov | Binding ligand linked drug delivery conjugates of tubulysins |
WO2008112873A3 (en) | 2007-03-14 | 2009-09-11 | Endocyte, Inc. | Binding ligand linked drug delivery conjugates of tubulysins |
WO2009002993A1 (en) | 2007-06-25 | 2008-12-31 | Endocyte, Inc. | Conjugates containing hydrophilic spacer linkers |
WO2009055562A1 (en) | 2007-10-25 | 2009-04-30 | Endocyte, Inc. | Tubulysins and processes for preparing |
WO2011069116A1 (en) | 2009-12-04 | 2011-06-09 | Endocyte, Inc. | Binding ligand linked drug delivery conjugates of tubulysins |
WO2011106639A1 (en) | 2010-02-25 | 2011-09-01 | Purdue Research Foundation | Psma binding ligand-linker conjugates and methods for using |
WO2012019123A1 (en) | 2010-08-06 | 2012-02-09 | Endocyte, Inc. | Processes for preparing tubulysins |
Non-Patent Citations (307)
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9745341B2 (en) | 2007-10-25 | 2017-08-29 | Endocyte, Inc. | Tubulysins and processes for preparing |
US20160016993A1 (en) * | 2013-03-01 | 2016-01-21 | Endocyte, Inc. | Process for preparing tubulysins |
US9771391B2 (en) * | 2013-03-01 | 2017-09-26 | Endocyte, Inc. | Process for preparing tubulysins |
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EP2209374A1 (en) | 2010-07-28 |
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